[0001] This invention relates to salts of compounds having antagonist activity at histamineH
2-receptors, to a process for the preparation thereof, to pharmaceutical compositions
containing them and to their use in therapeutics. More particularly the invention
is concerned with salts of histamineH
2-receptor antagonists formed with zinc complexes of certain carboxylic acids.
[0002] Compounds which have antagonist activity at histamineH
2-receptors are used in the treatment of conditions where there is an advantage in
lowering gastric acidity. Such conditions include duodenal and gastric ulceration,
reflux oesophagitis and Zollinger-Ellison syndrome. Ranitidine may also be used prophylactically
in surgical procedures, and in the treatment of allergic and inflammatory conditions
where histamine is a known mediator.
[0003] UK Patent Specification No. 2218987A, European Patent Specifications Nos. 350422
and 351348, and Spanish Patent Specifications Nos. 8804023 and 8900857 disclose zinc
derivatives of the histamineH
2-receptor antagonists cimetidine, etintidine, nizatidine, zaltidine and ranitidine,
covered by the general formula
[0004]

where R is respectively cimetidine, etintidine, nizatidine, zaltidine or ranitidine,
X is an anion of a pharmaceutically acceptable acid, a is an integer from 1 to 5,
and b is an integer from 1 to 7. ccording to UK Specification No. 2218987A, c is an
integer from 1 to 4, and d is 2a-c. According to European Specifications Nos. 350422
and 351348, and Spanish Specifications Nos. 8804023 and 8900857, c is zero or an integer
from 1 to 4, and d is 2a-c for monovalent acid anions, a-c for divalent acid anions
and zero or 2 when c is zero. Such compounds are described as having antiulcer properties.
[0005] Zinc compounds such as zinc chloride, zinc sulphate and zinc acexamate have been
described in for example Drug Development Research 17, 185-197 (1989) and Drugs Exptl.
Clin. Res. XV(2), 83-89 (1989) as being gastrohepatic protective agents, having a
stabilising action on mast cells, preserving gastric mucus and protecting the gastric
mucosa against the actions of known gastric irritants. Such zinc compounds thus have
a role in the treatment of gastric ulceration.
[0006] The only known stable form of zinc citrate is the 3:2 complex formed between zinc
and citric acid Zn
3(C
6H
50
7)
2- 2H
20, and this has been incorporated into toothpaste preparations as an antibacterial
and antiplaque agent.
[0007] It has now surprisingly been found that basic H
2-receptor antagonists will form stable salts with a simple 1: 1 stoichiometric complex
of zinc and a carboxylic acid such as citric acid, and that the salts thus formed
possess a useful and advantageous profile of activity.
[0008] The present invention thus provides novel salts of a basic H
2-receptor antagonist and a complex of zinc with a carboxylic acid selected from tartaric
acid, citric acid or an alkyl citric acid, and solvates of such salts. Salts in which
the H
2- receptor antagonist is ranitidine are however excluded from the scope of the invention.
[0009] The alkyl citric acid may be for example a C
1-6 alkyl citric acid, more particularly a C
1-3 alkyl citric acid (e.g. propylcitric acid).
[0010] In instances where the carboxylic acid can exhibit optical and/or geometrical isomerism,
the invention is intended to include all optical isomers including racemates, and/or
geometric isomers. Solvates, including hydrates, are also included within the scope
of the invention.
[0011] The preferred carboxylic acid for use in the invention is citric acid.
[0012] Suitable basic histamine H
2-receptor antagonists for salt formation with zinc-carboxylic acid complexes according
to the invention include imidazole derivatives; substituted aminoalkylbenzene, furan
and thiazole derivatives (e.g. dimethylaminomethyl-furanyl-methylthioethylamino compounds,
piperidinomethyl-phenoxyp- ropylamino compounds and dimethylaminomethyl-thiazolylmethylthioethylamino
compounds); guanidinothiazolyl derivatives including guanidinothiazolyl-methylthioethyl
and guanidinothiazolylmethylthioethylamino compounds; and guanidinopyrazolyl derivatives.
Examples of particular basic histamine H
2-receptor antagonists are cimetidine, famotidine, roxatidine, niperotidine, nizatidine,
mifentidine, zaltidine, ebrotidine, bisfentidine, 3-amino-4-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-3-cyclobutene-1,2-dione
(BMY 25368), 5-[3-[2-(2,2,2-trifluoroethyl)guanidino]pyrazol-1-yl]valeraimde, and
N-ethyl-N'-[3-(3-piperidinomethylphenoxy) propyl]urea.
[0013] Particular basic H
z-receptor antagonists for use according to the invention are cimetidine, famotidine,
nizatidine and roxatidine.
[0014] Cimetidine represents a preferred basic H
2-receptor antagonist for use according to the invention.
[0015] A preferred salt according to the invention is N-cyano-N'-methyl-N"-[2-[[(5- methyl-
1H-imidazoI-4-yI)methyl]thio]ethyl]guanidine 2-hydroxy- 1,2,3- propanetricarboxylate
zinc (2
+) complex, more specifically a 1: 1 complex, also known as cimetidine zinc citrate.
[0016] Salts according to the invention possess a particularly advantageous combination
of properties forthe treatment of gastrointestinal disorders, especially peptic ulcer
disease and other gastroduodenal conditions, for example non-ulcer dyspepsia.
[0017] Salts according to the invention possess antisecretory and cytoprotective properties.
Antisecretory activity may be demonstrated in vivo against histamine-induced gastric
acid secretion in the eidenhain pouch dog. Cytoprotective activity has been demonstrated
in vivo by the ability of the salts to inhibit ethanol-induced gastric lesions in
rats.
[0018] A further feature of salts according to the invention is that they are water soluble
and give stable aqueous solutions.
[0019] The salts of the invention are distinct chemical entities, and may be distinguished
from simple mixtures of the basic H
2-receptor antagonist and a complex formed between zinc and a carboxylic acid. This
distinction may be demonstrated on the basis of, for example, infra-red spectroscopy.
[0020] Salts according to the invention may be prepared by reacting the H
2-receptor antagonist with an appropriate zinc - carboxylic acid complex (e.g. zinc
citrate) in a suitable solvent such as water, and separating the salt thus formed
from the solution.
[0021] According to a further aspect the invention provides a salt of a basic H
Z- receptor antagonist and a complex of zinc with tartaric acid, citric acid, or an
alkyl citric acid, including solvates of such salts, said salt being prepared by reacting
the H
z-antagonist with an appropriate zinc - carboxylic acid complex.
[0022] The reaction between the H
2-receptor antagonist and an appropriate zinc- carboxylic acid complex to give a salt
according to the invention is preferably carried out at a temperature within the range
of 20 to 60°C, more preferably at room temperature. The resulting solution is cooled
(if appropriate) and altered or decanted from any residual solid. The required salt
may be obtained from the solution, by evaporation followed by extraction and trituration
of the resulting residue using for example an alcohol e.g. methanol or ethanol, a
ketone e.g. acetone and/or an ether e.g. diethyl ether.
[0023] The intermediate zinc - carboxylic acid complex may be prepared by reacting a zinc
base (e.g. zinc oxide or zinc carbonate) with an appropriate carboxylic acid (e.g.
citric acid) in a solvent such as water, conveniently at a temperature within the
range of 20 to 40°.
[0024] The intermediate zinc- carboxylic acid complex is preferably formed in situ and immediately
reacted with the H
z-antagonist to give a salt according to the invention.
[0025] The salts according to the invention may be formulated for administration in any
convenient way and the invention includes within its scope pharmaceutical compositions
containing a salt according to the invention adapted for use in human or veterinary
medicine. Such compositions, which are primarily intended for oral administration,
may be formulated in a conventional manner using one or more pharmaceutically acceptable
carriers or excipients.
[0026] For oral administration, the pharmaceutical compositions may take the form of, for
example, tablets (including chewable or suckable tablets) or capsules (of either the
hard or soft type). Such compositions may be prepared by conventional means with pharmaceutically
acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone
or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose
or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica);
disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents
(e.g. sodium lauryl sulphate). Tablets may be coated by methods well known in the
art. Liquid preparations for oral administration may take the form of, for example,
solutions, syrups or suspensions, or they may be presented as a dry product for constitution
with water or other suitable vehicle before use. Such liquid preparations may be prepared
by conventional means with pharmaceutically acceptable additives such as suspending
agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying
agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters,
ethyl alcohol orfractionated vegetable oils); and preservatives (e. g. methyl or propyl-p-hydroxybenzoates
or sorbic acid). The preparations may also contain buffer salts, flavouring, colouring
and sweetening agents as appropriate.
[0027] Tablets represent a preferred type of composition for oral use.
[0028] The dose at which the salts of the invention may be administered to man will depend
upon the nature of the histamine H
2-receptor antagonist, and the salts may in general be administered at doses based
on the normal dosage range at which the H
2- receptor antagonist concerned is therapeutically effective. Thus a suitable dosage
of a salt of a zinc - carboxylic acid complex in which the H
2-receptor antagonist is cimetidine may be for example 400mg to 1.6g per unit dose.
Similarly, for famotidine 15 to 80mg (more preferably 30 to 80mg), for nizatidine
80 to 500mg, and for roxatidine 80 to 500mg.
[0029] The unit dose may be administered, for example, one to four times daily, preferably
once or twice. The exact dose will depend on the nature and severity of the condition
being treated, and it will also be appreciated that it may be necessary to make routine
variations to the dosage depending on the age and weight of the patient.
[0030] The invention is illustrated by the following Example in which temperatures are in
°C. Thin layer chromatography (t.l.c.) was carried out on silica, eluting with the
solvent system indicated, and using u.v., iodop- latinate, potassium permanganate
and bromocresol green stain for detection.
Example
N-Cyano-N'-methyl-N"-[2-[[(5-methyl-1 H-imidazol-4-yl)methyl]thio]ethyl]guanidine[2-hydroxy-1,2,3-propanetricarboxylate
zinc (2+) complex (1:1)] (1:1)["Cimetidine zinc citrate" (1:1:1)].
[0031] Zinc oxide (1.63g) was dissolved in a solution of 2-hydroxy-1,2,3- propanetricarboxylic
acid (citric acid, 4.2g) in water (25ml) at room temperature. A slight exothermic
reaction occurred and after all the zinc oxide had dissolved, the solution was filtered
and N-cyano-N'-methyl-N"-[2-[[(5-methyl- 1 H-imidazol-4- yl)methyl]thio]ethyl]guanidine
(cimetidine, 5.05g) added. The mixture was diluted with water (30ml) and shaken until
almost all the solid had dissolved. The clear supenatant liquid was decanted away
from a small amount of residual gum which was discarded and the decanted liquid evaporated
to dryness to give a viscous gum. This was evaporated with hot methanol (50ml) and
the residue suspended in hot methanol (1 00ml). The suspension was filtered, the residue
washed well with hot methanol then ether and dried to give a solid (9.344g).
[0032] A portion of the solid (7.02g) was mixed with water (50ml) and the mixture heated
to 70° then filtered. The residue was washed with water and the combined filtrates
evaporated to dryness in vacuo to give a solid residue which was removed from the
flask with the aid of ether. The residue was ground to a powder, then mixed with ether
(100ml) and the mixture filtered. The residue was dried to give the title compound
(5.523g). T.I.c. (Methylene chloride:ethanol: 0.88 ammonia; 50:8:1) Rf 0.35 (cimetidine)
and Rf zero (zinc citrate).

Water assay indicated 1.36% H
20 = 0.38 mole.
[0033] The following Examples A to D illustrate pharmaceutical compositions according to
the invention in which the active ingredient is in particular cimetidine zinc citrate,
famotidine zinc citrate, nizatidine zinc citrate orroxati- dine zinc citrate. Other
compounds according to the invention may be formulated in a similar manner, using
an appropriate amount of active ingredient depending on the compound concened, with
suitable adjustments in the amounts of excipients and weights of the final dosage
forms.
Example A Tablets
[0034] Tablets may be prepared by the normal methods such as direct compression or wet granulation.
[0035] The tablets may be film coated with suitable film forming materials, such as hydroxypropyl
methylcellulose, using standard techniques.
(i) Direct Compression
[0036]

[0037] The cimetidine zinc citrate, microcrystalline cellulose, lactose and crosslinked
polyvinylpyrrolidone are sieved through a 500 micron sieve and blended in a suitable
mixer. The magnesium stearate is sieved through a 250 micron sieve and blended with
the active blend. The blend is compressed into tablets using suitable punches.
[0038] Famotidine zinc citrate may be formulated in a similar manner, using 75mg of the
active ingredient and appropriate weights of the excipients to give a tablet compression
weight of 400mg. Nizatidine zinc citrate and roxatidine zinc citrate may also be formulated
in a similar manner, using 290mg of the active ingredient and appropriate weights
of the excipients to give a tablet compression weight of 600mg.
(ii) Wet granulation
[0039]

[0040] The nizatidine zinc citrate, lactose and pregelatinised starch are blended together
and granulated with water. The wet mass is dried and milled. The magnesium stearate
and cross-linked polyvinylpyrrolidone are screened through a 250 micron sieve and
blended with the granule. The resultant blend is compressed using suitable tablet
punches.
Example B Suckable/Chewable Tablets
[0041]

[0042] The cimetidine zinc citrate, sweetener, flavour and mannitol are blended together
and granulated with a solution of polyvinyl pyrrolidone. The wet mass is dried, milled
and lubricated with magnesium stearate (meshed through a 250 micron sieve). The resultant
granule is compressed into tablets using suitable punches.
[0043] Suckable/chewable tablets containing famotidine zinc citrate (75mg), nizatidine zinc
citrate (290mg) or roxatidine zinc citrate (290mg) may be prepared in a similar way
with appropriate adjustment of the amount of mannitol to retain a compression weight
of 2000mg.
Example C Capsules
[0044]

[0045] The cimetidine zinc citrate and pregelatinised starch are screened through a 500
micron mesh sieve, blended together and lubricated with magnesium stearate (meshed
through a 250 micron sieve). The blend is filled into hard gelatin capsules of a suitable
size.

[0046] The famotidine zinc citrate and lactose are blended together and wet massed with
a solution of polyvinylpyrrolidone. The mass is dried and milled and blended with
the magnesium stearate and cross-linked polyvinylpyrrolidone (screened through a 250
micron mesh). The resultant blend is filled into hard gelatin capsules of a suitable
size.
Example D Syrup
[0047]

The hydroxypropyl methylcellulose is dispersed in a portion of hot purified water
together with the hydroxybenzoates and the solution is allowed to cool to room temperature.
The saccharin sodium, flavours and sorbitol solution are added to the bulk solution.
The famotidine zinc citrate is dissolved in a portion of the remaining water and added
to the bulk solution. Suitable buffers may be added to control the pH in the region
of maximum stability. The solution is made up to volume, filtered and filled into
suitable containers.
[0048] Syrups containing cimetidine zinc citrate, nizatidine zinc citrate or roxatidine
zinc citrate as the active ingredient may be prepared in a similar manner, replacing
famotidine zinc citrate with cimetidine zinc citrate (400.0mg), nizatidine zinc citrate
(290.0mg) or roxatidine zinc citrate (290.0mg) and making the volume up to 10.0ml.
1. A salt formed between a basic histamine H2-receptor antagonist and a complex of zinc with a carboxylic acid selected from tartaric
acid, citric acid and alkyl citric acids, or a solvate of such a salt, excluding salts
in which the basic H2- receptor antagonist is ranitidine.
2. A salt as claimed in Claim 1, wherein the carboxylic acid is citric acid.
3. A salt as claimed in Claim 1 or 2, wherein the basic histamine Hz-receptor antagonist is an imidazole derivative; a substituted aminoalkyl-benzene,
-furan or -thiazole derivative; a guanidinothiazolyl derivative; or a guanidinopyrazolyl
derivative.
4. A salt as claimed in Claim 3, wherein the basic histamine H2-receptor antagonist is selected from cimetidine, famotidine, roxatidine, niperotidine,
nizatidine, mifentidine, zaltidine, ebrotidine, bisfentidine, 3-amino-4-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-3-cyclobutene-1,2-dione,
5-[3-[2-(2,2,2-trifluoroethyl) guanidino]pyrazol-1-yl]valeramide and N-ethyl-N'-[3-(3-piperidinomethylphenoxy)propyl]urea.
5. A salt as claimed in Claim 3, wherein the basic histamine H2-receptor antagonist is cimetidine.
6. A salt as claimed in any of Claims 1 to 5, wherein the complex of zinc and the
carboxylic acid is a 1: 1 complex.
7. N-cyano-N'-methyl-N"-[2-[[(5-methyl-1H-imidazol-4-yl)methyl]thio]ethyl]guanidine
2-hydroxy-1,2,3-propanetricarboxylate zinc (2+) complex, and solvates thereof.
8. A process for the preparation of a salt as claimed in any of Claims 1 to 7, which
comprises reacting the basic histamine Hz-receptor antagonist with a complex of zinc and the carboxylic acid in a suitable
solvent and separating the salt thus formed from the solution.
9. A pharmaceutical composition comprising a salt as claimed in any of Claims 1 to
7, together with at least one pharmaceutically acceptable carrier or excipient.
10. A salt as claimed in any of Claims 1 to 7, for use as an active therapeutic agent.
Claims for the following Contracting State : ES
1. A process for the preparation of a salt formed between a basic histamine H2- receptor antagonist and a complex ofzincwith a carboxylic acid selected from tartaric
acid, citric acid and alkyl citric acids, or a solvate of such a salt, excluding salts
in which the basic H2-receptor antagonist is ranitidine, which comprises reacting the basic histamine Hz-receptor antagonist with a complex of zinc and the carboxylic acid in a suitable
solvent and separating the salt thus formed from the solution.
2. A process as claimed in Claim 1, wherein the solvent is water.
3. A process as claimed in Claim 1 or 2, wherein the reaction is carried out at a
temperature of 20 to 60°C.
4. A process as claimed in any of Claims 1 to 3, wherein the carboxylic acid is citric
acid.
5. A process as claimed in any of Claims 1 to 4, wherein the basic histamine H2- receptor antagonist is an imidazole derivative; a substituted aminoalkyl-benzene,
-furan or -thiazole derivative; a guanidinothiazolyl derivative; or a guanidinopyrazolyl
derivative.
6. A process as claimed in Claim 5, wherein the basic histamine H2-receptor antagonist is selected from cimetidine, famotidine, roxatidine, niperotidine,
nizatidine, mifentidine, zaltidine, ebrotidine, bisfentidine, 3-amino-4-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-3-cyclobutene-1,2-dione,
5-[3-[2-(2,2,2-trifluoroethyl)guanidino]pyrazol-1-yl]valeramide and N-ethyl-N'-[3-(3-piperidinomethylphenoxy)propyl]
urea.
7. A process as claimed in Claim 5, wherein the basic histamine H2-receptor antagonist is cimetidine.
8. A process as claimed in any of Claims 1 to 7, wherein the complex of zinc and the
carboxylic acid is a 1:1 complex.
9. A process as claimed in any of Claims 1 to 8 for the preparation of N-cyano- N'-methyl-N"-[2-[[(5-methyl-1H-imidazol-4-yl)methyl]thio]ethyl]guanidine
2- hydroxy- 1,2,3-propanetricarboxylate zinc (2+) complex, and solvates thereof.